Immunotherapies are formulated with the intention of augmenting the activity of the immune system to eliminate cancerous cells. The tumor microenvironment (TME) has been a central area of investigation in tumor immunotherapy research. Therefore, the aim of this chapter was to review the role of the TME in response to cancer immunotherapies. Monoclonal antibody-based (mAb) therapies represent the most rapidly expanding facet of immunotherapy at present. These medications have the capacity to attract T cells to the tumor site, directly confront tumor cells, alter the host’s response to the tumor, and consequently impede or potentially eradicate the tumor. Antibodies targeting CTLA-4 and PD-1, along with CAR-T-cell therapy, present encouraging strategies in which specific elements of the immune system can be modulated to counteract suppression and effectively target tumors. Comprehending the tumor microenvironment (TME) assumes critical importance in refining immunotherapy and constitutes a pivotal aspect of cancer treatment strategies. Furthermore, insights into the TME contribute to identifying predictive biomarkers that inform treatment decisions. The diversity of TME components across different cancers and even within the same cancer type underscores the necessity for personalized therapeutic approaches. Subsequent therapies can be customized based on individual TME profiles, taking into account variations in immune cell composition, cytokine milieu, and other microenvironmental factors.